: Toxicant exposure, particularly environmental exposure to compounds that cause free radical toxicity or exocytotoxicity, may contribute to the development Amyotrophic Lateral Sclerosis (ALS). Endogenous susceptibility factors affecting anti-oxidant defenses also appear likely to increase the risk of developing ALS. The long term objective of this study is to investigate the role of environmental toxicants and genetic susceptibility factors in the etiology of ALS. Specific aims include: (1) to examine the relationship between the development of ALS and environmental exposure to such as heavy metals and other neurotoxicants; (2) to investigate the etiologic role of deficient endogenous antioxidant defenses in ALS including genetic alterations of the copper-zinc superoxide dismutase (SOD1) enzyme and a relative deficiency of dietary antioxidants; (3) to evaluate the extent to which other neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease aggregate among family members of ALS patients; and (4) to estimate the incidence of ALS in a large racially diverse population. To address these aims we propose to conduct a case-control study of 175 incident ALS and 550 age-and gender- comparable control subjects. Data will be derived 2 sources for all subjects: an in-person structured interview and self-administered food frequency questionnaire. In addition, all 175 ALS cases and a subset of 350 control subjects will undergo measurement of bone lead stores using K x-ray fluorescence and will have a venous blood sample drawn for SOD1 genotyping and DNA banking. The collection of detailed information regarding the duration and timing of environmental exposures will enable the evaluation of dose response trends and estimation of latent periods between putative exposure and the development of ALS. It is hoped that the proposed study will advance knowledge of neurotoxic and endogenous susceptibility factors that are important in the etiology of ALS.